PROJECT SUMMARY/ABSTRACT The clinical and public health implications of this proposed trial are far-reaching as the science over the last decade has confirmed that estrogen provides substantial benefits with low risk to women especially when initiated in the perimenopausal or early postmenopausal period. However, the majority of women entering menopause have a uterus requiring co-treatment with progestogen to counter estrogen-induced endometrial hyperplasia. Co-treatment with progestogen creates a limiting factor for postmenopausal hormone therapy (HT) since relative to estrogen alone, traditional progestogen-containing HT regimens carry the greatest health risks for women, including venous thromboembolism (VTE) and breast cancer. However, as a component of tissue selective estrogen complex (TSEC), a new class of agents, estrogen can now be delivered in a progestogen-free regimen without risks from progestogen exposure. As a new class of innovative medications, TSEC therapy provides a novel approach for the treatment of menopausal symptoms by partnering a selective estrogen receptor modulator (SERM) with estrogen to achieve optimal clinical results based on the blended tissue-selective activity profile. The effect of combined bazedoxifene (BZA), a third generation SERM with conjugated estrogens (CE) on breast, endometrium, bone, lipid biosynthesis and venous thrombosis are unique with optimization of safety and efficacy. A series of phase 3 randomized controlled trials have shown that BZA/CE (FDA approved) is effective in preventing osteoporosis and providing relief of vasomotor and vaginal symptoms while ensuring endometrial safety. BZA/CE does not stimulate endometrial tissue and the rate of cumulative amenorrhea with BZA/CE is comparable with placebo as is the incidence of endometrial hyperplasia (<1%). In addition, BZA/CE does not stimulate breast tissue and does not increase mammographic density relative to placebo; the incidences of VTE (deep vein thrombosis and pulmonary embolism) and stroke are similar to placebo. To date, randomized controlled trials have been conducted with traditional progestogen- based HT. Deploying the innovative progestogen-free formulation of BZA/CE to protect the uterus in women without a hysterectomy is the next step beyond traditional HT (progestogen opposed estrogen therapy) in providing safe and effective therapy for women with the new TSEC class of agents, the effects of which on atherosclerosis progression are unknown. This proposal seeks to address this major gap in our knowledge and to cease upon this unique public health opportunity. The specific aim of our proposal is to conduct a randomized, double-blinded, placebo-controlled trial in 360 healthy postmenopausal women with a uterus within 6 years of menopause and less than 60 years of age without clinical cardiovascular disease and diabetes mellitus randomized to BZA 20 mg/CE 0.45 mg or placebo for a treatment period of 2 to 4.5 years to determine the effects of TSEC therapy on the progression of subclinical atherosclerosis measured as change in carotid artery intima-media thickness and carotid arterial stiffness as trial end-points.